WO2006117977A1

WO2006117977A1 - Process for production of carbostyril compound

Info

Publication number: WO2006117977A1
Application number: PCT/JP2006/307461
Authority: WO
Inventors: Kengo Kawasaki; Takayuki Ikeda; Kenji Sekine; Norio Fukuda
Original assignee: Otsuka Pharmaceutical Co., Ltd.
Priority date: 2005-04-28
Filing date: 2006-04-07
Publication date: 2006-11-09
Also published as: US20070299262A1; IL179235A0; KR101265877B1; US7718806B2; CN1989108A; IL179235A; JP3892894B2; CN1989108B; KR20080019151A; JP2006328045A

Abstract

Disclosed is an improved process which can produce a carbostyril compound of the formula (1) or a salt thereof, which is useful as a pharmaceutical agent, more safely with higher efficiency. An improved process for producing a carbostyril compound comprising the steps of adding a high boiling solvent to a compound of the formula (4) and refluxing the resulting mixture under heating in hydrochloric acid to produce a compound of the formula (5) safely and acylating the compound of the formula (5) to produce a carbostyril compound of the formula (1).

Description

Method for producing carbostyril compound

Technical field

[0001] The present invention relates to an improved method for producing a carbostyril compound, which produces the following carbostyril compound which is useful as a therapeutic agent for gastric ulcer and the like more safely and efficiently.

Background art

[0002] The carboschirirui compound of the present invention is a carboschirirui compound represented by the following formula (1) (chemical name: 2— (4 black benzoylamino)-3- [2 (1Η) -quinolinone 4-yl] propionic acid), a drug that exhibits excellent therapeutic effects on gastric mucosal lesions appearing during gastric ulcer, acute gastritis, or acute exacerbation of chronic gastritis.

[0003] [Chemical 1]

[0004] As a method for producing a carbostyril compound represented by the formula (1) of the present invention, for example, a method represented by the following reaction formula 1 is known (Patent Document 1). That is, the compound of formula (2) is reacted with the compound of formula (3) in the presence of a base such as sodium ethoxide to obtain the compound of formula (4), and this compound is hydrolyzed with a mineral acid such as hydrochloric acid. And decarboxylating to produce the compound of formula (5), and then saponifying with 4-chlorobenzoyl chloride of formula (6) to produce the desired compound of formula (1).

[0005] [Chemical 2] Reaction formula 1

According to the above method, the step of producing the compound of the formula (5) from the compound of the formula (4) is required to heat and reflux the compound (4) in, for example, 20% hydrochloric acid. In the process, ethanol, carbon dioxide, acetic acid, and ethyl acetate are by-produced as the reaction proceeds. For this reason, the reaction interface is bubbling violently due to the generated carbon dioxide gas, and this foam does not disappear immediately. In particular, when the amount of hydrochloric acid relative to compound (4) is small, a rapid increase in the interface due to the bubbles is observed, and it is often difficult to carry out the refluxing continuously. In addition, the sudden rise of the interface caused by such bubbles involves the risk of bumping, and safety is a major problem when producing the target carbostyryl compound (1) in large quantities. Moreover, in order to avoid such foaming, it is necessary to suppress heating, and the heat necessary to accelerate the reaction cannot be sufficiently applied. In addition, ethanol, ethyl acetate and the like by-produced in the above reaction step lower the reflux temperature, causing a problem that causes a delay in the reaction rate. Therefore, how to safely and efficiently carry out the process leading to this compound (4) force compound (5) is an important factor in the industrial production of the carboschiril compound represented by the formula (1) of the present invention. Become.

Patent Document 1: Japanese Patent Application Laid-Open No. 60-19767

Disclosure of the invention Problems to be solved by the invention

[0007] Therefore, in the process of producing the compound of the formula (4) or the salt power of the formula (5) or the salt thereof in the above conventional method, even when a large amount is synthesized by suppressing the rise of the interface due to foaming. As a result of various investigations to find a method that can be safely and efficiently produced, by adding a specific substance to the reaction system during the reaction, foaming is suppressed and the safer and useful compound (5) or a salt thereof is efficiently produced. Thus, it was found that by subjecting the compound (5) or a salt thereof to an acylate, a desired carbostyril compound of the formula (1) or a salt thereof can be obtained, and the present invention was completed. It was.

[0008] An object of the present invention is to provide an improved method by which a carbostyril compound of formula (1) or a salt thereof useful as a medicament can be produced more safely and efficiently.

In addition, the compound of formula (5) or a salt thereof produced as an intermediate in the production method of the present invention is an intermediate substance for producing a desired carbostyril compound or a salt thereof of formula (1). It is desired that the crystal can be easily and easily removed from the reaction system. Moreover, in order to be suitable for storage as an intermediate substance for producing a desired carboschiril compound of the formula (1) or a salt thereof, it is desired that the drying can be performed more easily and efficiently. .

Another object of the present invention is to provide a compound of the formula (4) during a series of steps for producing the desired carbostyril compound of the formula (1) or a salt thereof from the compound of the formula (2) or a salt thereof. In the process of producing a compound of the formula (5) or a salt thereof from the compound or a salt thereof, heating in the presence of a high-boiling point solvent suitable for this step causes a sudden reaction caused by bubbles generated during the reaction. The present invention provides a method for more safely producing the desired carbostyryl compound (formula (1)) or a salt thereof by suppressing the rise of the interface and bumping accompanying this. Another object of the present invention is to improve the above-mentioned problem of preventing bumping, while maintaining the reflux temperature while removing by-products such as ethanol and ethyl acetate in the reaction step as necessary. The present invention also provides a method for producing the compound 5) or a salt thereof more efficiently.

A further object of the present invention is to provide a dihydrochloride dihydrate of the compound of formula (5) as the desired intermediate. Means for solving the problem

[0010] According to the present invention, the compound of formula (5) or a salt thereof can be produced safely by heating the compound of formula (4) or a salt thereof in the presence of a high-boiling solvent under acidic conditions. The production of the compound of formula (5) or a salt thereof can be carried out more efficiently by maintaining the heating temperature, particularly the reflux temperature, while removing by-products such as ethanol and ethyl acetate in the reaction step as necessary. Can do. Subsequently, the compound (5) or a salt thereof is acylated with 4 chlorobenzoyl chloride of the formula (6) to obtain the target carbostyryl compound of the formula (1) or a salt thereof.

That is, according to the present invention, when the compound of the formula (4) or a salt thereof is heated under acidic conditions to derive the compound of the formula (5) or a salt thereof, the reaction is performed with a specific high boiling point solvent. By doing so, the high boiling point solvent functions as an antifoaming agent, suppresses undesirable foaming, and adds sufficient caloric heat to accelerate the reaction.

[0012] In the reaction leading to the compound of the formula (4) or a salt power thereof, or to the compound of the formula (5) or a salt thereof, a substance having a relatively low boiling point such as ethanol or ethyl acetate is added as the reaction proceeds. Therefore, if the reaction is continued as it is, the heating temperature, particularly the reflux temperature is lowered, and the reaction is delayed because sufficient heat cannot be applied. Therefore, it is necessary to maintain the reaction efficiency by extracting the low-boiling point substances generated as a by-product from the reaction system. According to the present invention, by maintaining the heating temperature, particularly the reflux temperature and improving the efficiency of the reaction to improve the foaming problem, the temperature is maintained while removing by-products in the reaction process as necessary. A method for producing the compound of the formula (5) or a salt thereof more efficiently can be provided.

[0013] According to the present invention, the step of heating the compound of the formula (4) or a salt thereof to obtain the compound of the formula (5) or a salt thereof is performed in water, and Z or of the formula (5) Reaction process power to obtain a target carbostyril compound of the formula (1) or a salt thereof by subjecting the compound or a salt thereof to acylation The above formula (5) carried out in water, an organic solvent or a mixture thereof Or a salt thereof, or a method for producing a carbostyril compound of the formula (1) or a salt thereof.

[0014] Further, according to the present invention, in the step of heating the compound of the formula (4) or a salt thereof to obtain the compound of the formula (5) or a salt thereof, a reaction in which the heating reaction is carried out in the presence of hydrochloric acid ( 5) A method for producing a compound or a salt thereof can be provided.

[0015] According to the present invention, the high boiling point solvent used in the step of heating the compound of the formula (4) or a salt thereof to obtain the compound of the formula (5) or a salt thereof is normal octanol and Z Alternatively, it is possible to provide a method for producing a compound of formula (5) or a salt thereof which is aacetophenone.

[0016] According to the present invention, the compound of the formula (5) or a salt thereof obtained by the production method of the present invention is a dihydrochloride dihydrate of the compound represented by the formula (5). It is possible to provide new substances with features.

[0017] The high boiling point solvent used in the present invention may be any substance that can perform the above-described operation without any trouble.

However, according to the study of the industrial level production method by the present inventors, the solvent is a substance that can suppress the rise of the interface due to foaming caused by the generation of the carbon dioxide gas, and It must azeotrope with the solvent added with the acid used in the reaction, have a higher specific gravity than the solvent added with the acid, and be separated without mixing with the solvent added with the acid, and have a higher boiling point than the solvent added with the acid. Has been found to be suitable for that purpose.

[0018] The inventors of the present invention can preferably illustrate hydrochloric acid as the acid used in the production method of the present invention, as shown in the examples below, and the corresponding high-boiling solvent has a specific gravity higher than that of hydrochloric acid, for example. It has been found that normal otatanol and Z or acetophenone, which are high-boiling substances that are not mixed with small hydrochloric acid, are more suitable for that purpose.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the reaction leading to the compound of formula (4) or a salt thereof by acid hydrolysis to the compound of formula (5) or a salt thereof is carried out by using a high-boiling solvent in the presence of a hydrolysis catalyst. It is done by adding. Hydrolysis catalysts include halogen hydrofluoric acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, mineral acids such as sulfuric acid and phosphoric acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid. As a particularly preferable catalyst, hydrochloric acid can be exemplified.

These catalysts can be used singly or in combination of two or more. In addition, water contained in hydrochloric acid, which may be used as the reaction solvent with a solvent such as water in which the acid is dissolved, is particularly preferred as the solvent for the reaction.

The amount of acid used as the catalyst is not particularly limited. For example, hydrochloric acid is used as the acid. In this case, it can also be used as a solvent for the reaction, and the concentration is usually

12 to 36%, preferably 18 to 22% of hydrochloric acid is usually used in an amount of 6 parts by volume or more, preferably 8 parts by volume or more based on 1 part by weight of the compound of the formula (4) or a salt thereof.

[0020] The high boiling point solvent that can be used in the present invention results from the generation of carbon dioxide gas by-produced in the step of heating and reacting the compound of the above formula (4) or a salt thereof under acidic conditions. It exists as a substance (including defoaming effect) that can suppress the rise of the interface due to foaming (including defoaming), does not mix with the solvent to which the acid is added, and is used for the reaction. There is no particular limitation as long as it is a substance that has physico-chemical properties that azeotropes with the solvent to which the acid is added and has a higher boiling point and lower specific gravity than the solvent to which the acid is added. . More specific examples of the high boiling point solvent include normal pentanol, 2-pentanol, 3-pentanol, 3-methyl-1-butanol, normal hexanol, 2-methyl-1-pentanol, 2-ethyl-1-butanol, and 3 Ptanol, normal otathanol, normal nonanol, 3, 5, 5 trimethyl- 1 hexanol, normalde force norm, normalunde force norl, normal dodecanol etc. For example, when hydrochloric acid is used also as an acid catalyst and a solvent for the reaction, normaloctanol and acetophenone having physical and physical properties satisfying the above conditions are more suitable. It can be used as a high boiling point solvent.

The amount of the high-boiling solvent used is not particularly limited, and the preferred amount varies depending on the degree of foaming, the shape of the reaction vessel, etc., but with respect to 1 part by weight of the compound of formula (4) or a salt thereof, Usually, a range force of about 0.1 to 3 parts by volume, preferably about 0.1 to 1 parts by volume is also selected. The above reaction is usually carried out by heating from 80 ° C. to the reflux temperature of the reaction solvent, preferably 100 ° C. and the reaction solvent, and is usually completed in about 6 to 24 hours.

[0021] The high-boiling solvent used in the production method of the present invention has the effect of suppressing an increase in the reaction liquid interface in the step of heating and reacting the compound of formula (4) or a salt thereof under acidic conditions. Since the compound of formula (5) or a salt thereof can be produced safely and the volumetric efficiency of the reactor can be greatly increased, it can be used for mass synthesis of the compound of formula (5) or a salt thereof. It can be suitably used. In the present invention, from the compound of the formula (4) or a salt thereof, the compound of the formula (5) In the reaction leading to the compound or its salt, the compound of the formula (5) or its salt is more efficiently produced by maintaining the heating temperature, particularly the reflux temperature while removing by-products in the reaction step as necessary. be able to.

If the reaction is performed using, for example, a Dean's Stark apparatus, the above two conditions can be satisfied at the same time, which can be suitably used as an industrial production method.

Specifically, at the reflux temperature, the azeotropic water and high-boiling point solvent condensate are separated into two layers in the apparatus, and the high-boiling point solvent used in the production method of the present invention is separated into the upper layer. The resulting low-boiling substances are distributed to the lower layer (aqueous layer; eg hydrochloric acid). Therefore, by extracting only the lower layer little by little, low-boiling substances are removed from the reaction system, the necessary high reflux temperature is maintained and reaction delay is avoided, and only the upper-boiling solvent in the upper layer is circulated to the reaction tank. And the rise of the interface due to foaming can be continuously suppressed. After completion of the reaction, the high-boiling solvent and water (including acid) are removed by extracting the condensate out of the reaction system and separating it without circulating the high-boiling solvent to the reaction vessel. Each can be recovered. In addition, the collected product can be reused as it is or after appropriate processing.

In the present invention, the salt of the compound of the formula (5) obtained from the compound of the formula (4) or a salt thereof using a production method leading to the compound of the formula (5) or a salt thereof is It was found to be a dihydrochloride dihydrate of a compound of formula (5), which has been conventionally known!

The dihydrochloride dihydrate of the compound of the formula (5) of the present invention has better filterability than other known monohydrochlorides of the compound of the formula (5), and the crystals can be taken out by a centrifuge or the like. It will be easy. In addition, since the dihydrochloride dihydrate of the compound of formula (5) has good filterability, it can be obtained as a low-liquid-content, low-humidity wet substance, so that impurities can be easily removed to the filtrate side. Since it can be obtained with a high degree of purity and can be easily dried, it can be mass-produced more efficiently and is a novel substance that is more suitable for storage as an intermediate of the target compound.

[0023] As another production method for deriving a compound of formula (4) or a salt thereof from a compound of formula (5) or a salt thereof, a compound of formula (4) or a salt thereof is mixed with hydrochloric acid and acetic acid. When heated to the compound of formula (5), the increase in the interface due to foaming is suppressed to an acceptable level in industrial mass production without adding a high-boiling solvent. It was also found that the reaction can be completed in a relatively short time. Specifically, 5 to 9 parts by volume of hydrochloric acid, preferably 8 to 9 parts by volume, and 2 to 5 parts by volume of acetic acid, preferably 2.5 parts per 1 part by weight of the compound of formula (4) or a salt thereof. ~ 3.5 volume parts, and the total amount of hydrochloric acid and acetic acid should be about 10-12 volume parts. The concentration of hydrochloric acid used at this time is usually 12% to 36%, preferably 18 to 22%. The reaction is usually performed by heating to 100 ° C. or higher, preferably to the reflux temperature. If the reaction is carried out using the above specific conditions, the desired compound of the formula (5) can be obtained in a short reaction without substantially reducing the yield.

Another object of the present invention is to prepare a compound of the formula (4) or a salt thereof in a step of producing a compound of the formula (4) or a salt thereof from the compound of the formula (4) or a salt thereof by mixing hydrochloric acid and acetic acid. The present invention provides an efficient production method suitable for industrial mass production when heated in liquid to lead to a compound of formula (5).

Furthermore, in the present invention, the compound of the formula (4) or a salt thereof is heated to be derivatized into the compound of the formula (5) or a salt thereof, and then the compound of the formula (5) or a salt thereof is converted to the 4 Reaction with oral benzoyl chloride provides the desired carbostyril compound of formula (1). This reaction can be easily performed by a conventional amide bond formation reaction. In addition, by appropriately selecting the solvent to be used, after completion of the reaction, the reaction liquid is cooled, and if necessary, the reaction liquid is neutralized, and the precipitated crystals are collected by filtration to obtain a carbostyril compound. (1) or its salt can be easily separated and collected.

Accordingly, the method of the present invention can produce the carboschiri louis compound of formula (1) safely and in large quantities, and is excellent as a method for producing an industrial carbos chilly compound (1).

The above reaction is usually performed using a conventional base. Examples of the base include alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide hydroxide, Cesium hydroxide, etc.), alkali metal carbonates (eg, lithium carbonate, sodium carbonate, carbonated lithium, cesium carbonate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium) tert-butoxide, sodium t ert pentoxide, etc.), alkali metal hydrides (eg, sodium hydride, hydrogenated) Potassium, etc.), alkali metal acetates (eg, sodium acetate, potassium acetate, etc.), trialkylamines [eg, trimethylamine, triethylamine, Nethyldiisopropylamine, etc.], pyridine, quinoline, piperidine, imidazole, Picoline, dimethylaminopyridine, dimethylamino, N-methylmorpholine, 1,5 diazabicyclo [4.3.0] non-one (DBN), 1,4-diazabicyclo [2.2.2] octane-5 —Yen (0 8 0), 1, 8 —Jazabicyclo [5. 4. 0] Wunde force—7 Yen (DBU). These base groups can be used alone or in combination of two or more.

In the above reaction, the ratio of the compound of the formula (5) or a salt thereof and the 4-clobenbenzoyl chloride of the formula (6) is at least equimolar, preferably equimolar to the latter with respect to the former. 2 times mole. In addition, the base should be used in an amount of at least equimolar with respect to the 4-chlorobenzoic acid lid of formula (6).

As the solvent used in the above reaction, a conventional solvent can be used, and examples thereof include water, methanol, ethanol, propanol, butanol, acetone, acetonitrile, and ethyl acetate, one kind alone or a mixture of two or more kinds. It can also be used.

The above reaction is usually carried out at about −10 to: about L00 ° C., preferably about 0 to 36 ° C., and is usually completed in about 5 minutes to 15 hours to obtain the desired carboschirily compound of formula (1). Obtainable.

In the present invention, the raw material compounds (2) to (5) in Reaction Scheme 1 may be an appropriate salt or an appropriate reactive derivative.

The carbostyril compound or salt thereof represented by the formula (1) of the present invention includes stereoisomers, optical isomers and solvates (hydrates, ethanolates, etc.).

The carbostyril compound represented by the formula (1) of the present invention can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and the present invention includes this acid addition salt. . In the above, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, and tartaric acid. Examples include acids, citrate, malonic acid, methanesulfonic acid, benzoic acid, trifluoroacetic acid, benzenesulfonic acid, formic acid, toluenesulfonic acid and other organic acids, or amino acids (eg, alginine, aspartic acid, glutamic acid, etc.) Can do.

[0026] The carbostyril compound represented by the formula (1) of the present invention is a pharmaceutically acceptable base. A salt can be easily formed by allowing the chemical compound to act. Examples of such salts include metal salts such as alkali metal salts (for example, sodium salts and potassium salts) and alkaline earth metal salts (for example, calcium salts and magnesium salts); ammonium salts; organic base salts (For example, trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, dicyclohexylamine salt, N, N, -dibenzylethylenediamine salt, etc.). Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

[0027] In addition, the carbostyril compound represented by the formula (1) of the present invention is more efficiently absorbed into the living body by reducing the particle diameter with a normal pulverizer (for example, an atomizer). It can be carried out. As a method for producing a powder having a reduced particle size of the carboschirirui compound, the particle size can be easily reduced by a known method well known to those skilled in the art. The method can be refined by a ceramic mill under suitable conditions such as the mill rotation ratio or the feed ratio of the carboschilli compound (1). It can also be refined by passing through an air jet mill with an appropriate supply air pressure while rotating at an appropriate supply ratio or rotation ratio of the carboschilli compound represented by the formula (1) of the present invention. Is possible. By this method, a pulverized product of carbostilil compound represented by the formula (1) of the present invention having an average particle size of 0.5 to 5; ζ ΐη and 90% cumulative particle size of 10 μm or less suitable for formulation is obtained. be able to.

Example

[0028] Hereinafter, the present invention will be described in more detail with reference to examples.

[0029] Example 1

2-acetoamide 2-ethoxycarbol 3— [2 (1H) quinolinone 4-yl] ethyl ethion propionate (compound of formula (4)) 40 g, 20% hydrochloric acid 400 ml and normaloctanol 12 ml were added, Using the Dean 'Stark device, the upper layer containing normal octanol out of the condensate separated in the device was circulated to the reactor, and only the lower layer was refluxed for 6 hours while distilling about 10 to 20 ml per hour. . After 6 hours of reflux, the normal octanol was distilled off and then refluxed for 2 hours while distilling about 10 to 20 ml per hour. After cooling to below 20 ° C, the precipitated crystals were collected by filtration. The obtained crystals are washed with acetone and heated at about 60 ° C. After drying in air, 35.4 g (yield 97.1%) of 2-amino-1- (2 (1H) -quinolinone-4-yl] propionic acid dihydrochloride dihydrate (of formula (5) Compound dihydrochloride dihydrate) was obtained. Melting point: 295 ° C (decomposition)

1H-NMR (DMSO-d, δ ppm)

6

11.81 (brs, IH), 8.67 (brs, 3H), 7.85 (d, J = 8.3 Hz, IH), 7.54 (t, J = 7.6Hz, IH), 7.3 8 (d, J = 8.3Hz, IH) , 7.24 (t, J = 7.6 Hz, IH), 6.51 (s, IH), 4.53—4.13 (m, IH), 3.37 (d, J = 7.3 Hz, 2H)

Moisture; 10.6% (theoretical value: 10.6%)

Hydrochloric acid content; 21.0% (theoretical value: 21.4%)

Elemental analysis; measured value C: 41.98%, H: 5.04%, N: 8.07%

Calculated C: 42.24%, H: 5.31%, N: 8.21% (C H N CI O)

12 18 2 2 5

[0030] Jewelery 12

Compound of formula (4) 80. Add 360 ml of water, 360 ml of concentrated hydrochloric acid, and 60 ml of acetophenone to Og, and use acetophenone in the condensate separated in the apparatus using Dean's Stark device. The upper layer was circulated in the reaction vessel, and the lower layer was reacted for 10 hours at the reflux temperature (103 to 106 ° C.) while part of the lower layer was distilled off. After the reaction, the solution was concentrated and distilled to recover acetophenone. After cooling to below 20 ° C, the precipitated crystals were collected by filtration. The obtained crystals were washed with acetone and then dried in hot air at about 60 ° C. to obtain the desired compound of formula (5) as dihydrochloride dihydrate (yield: 95.6%) ).

[0031] Example 3

2-Amino 3— [2 (1H) quinolinone 4-yl] propionic acid dihydrochloride dihydrate (dihydrochloride dihydrate of the compound of formula (5)) in 30 g, water 600 ml and 25% water 60 ml of an aqueous sodium oxide solution was added and dissolved. Next, a 90 ml acetone solution of 23 g (compound of formula (6)) of 4-clobenbenzoyl chloride was added dropwise under ice cooling. After completion of the dropwise addition, the solution was acidified with hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and acetone, and dried with warm air at about 80 ° C. to obtain 31.6 g (yield 96.9%) of a carbostyril compound of formula (1).

[0032] Example 4

Add 90 ml of water, 90 ml of concentrated hydrochloric acid and 60 ml of acetic acid to 20 g of the compound of formula (4) and heat for 6 hours. The reaction was carried out at reflux. 125 ml was concentrated and distilled off, and after cooling to 20 ° C. or lower, the precipitated crystals were collected by filtration. The obtained crystals were washed with acetone and dried with warm air at about 60 ° C, to give the compound of formula (5) (yield: 96.2%) ₀

Industrial applicability

[0033] According to the method of the present invention, the danger of bumping can be avoided by using a high-boiling solvent, so that a desired carbostyril compound or salt thereof of the formula (1) can be produced safely, In addition, the volumetric efficiency of the reactor can be greatly increased, which is extremely effective for mass synthesis.

[0034] According to the method of the present invention, the high-boiling solvent used is easily recovered by distilling off during the reaction, or by separating the liquid after distilling off the reaction. In addition, the acid (hydrochloric acid) filtrate after solid-liquid separation can be reused without discarding the majority of the fractions except the initial fraction by performing a simple distillation operation. Since it can be recovered as (hydrochloric acid), adverse effects on the environment can be reduced.

[0035] According to the method of the present invention, the post-treatment after completion of the reaction can obtain the compound of formula (5) or a salt thereof in a high yield by a simple operation of crystal filtration after cooling. It is effective for the large-scale synthesis of the carboschiril compound of formula (1) or a salt thereof.

[0036] The dihydrochloride dihydrate of the compound of the formula (5) of the present invention is crystallized by a centrifuge or the like, which has better filterability than other known monohydrochlorides of the compound of the formula (5). It becomes easy to take out. In addition, since the dihydrochloride dihydrate of the compound of formula (5) has good filterability, it can be obtained as a low-liquid-content, low-humidity wet substance, so that impurities can be easily removed to the filtrate side. Since it can be obtained with a high degree of purity and can be easily dried, it can be mass-produced more efficiently and is a novel substance that is more suitable for storage as an intermediate of the target compound.

[0037] According to the method described in the present specification, as another production method leading from the compound of the formula (4) or a salt thereof to the compound of the formula (5) or a salt thereof, the compound of the formula (4) or By heating the salt in a mixture of hydrochloric acid and acetic acid at a certain ratio, the increase in the interface due to foaming can be suppressed to an acceptable level in industrial mass production without adding a high-boiling solvent. In addition, the reaction can be completed in a relatively short time.

Claims

A process for producing a compound of the formula (5) or a salt thereof, characterized by subjecting the compound of the formula (4) or a salt thereof to the following steps (a) or (a) and (b): (A) A step of heating the compound of the formula (4) or a salt thereof in the presence of a high-boiling solvent under acidic conditions (b) A step of distilling off reaction by-products in the step (a).

[Chemical 1]

[Chemical 2]

A step of obtaining a compound of the formula (5) or a salt thereof by subjecting the compound of the formula (4) or a salt thereof to the following steps (a) or (a) and (b): A method for producing a compound of the formula (1) or a salt thereof characterized by being subjected to a process:

(a) A step of heating the compound of formula (4) or a salt thereof in the presence of a high boiling point solvent under acidic conditions

(b) a step of distilling off reaction by-products in the step (a);

(c) A step of reacting a compound of formula (5) or a salt thereof with 4-chlorobenzoyl chloride under basic conditions.

[Chemical 3] NHCOCH3

'-COOEt

In OOEt

(Four)

[Chemical 4]

[Chemical 5]

The process according to claim 1 or 2, wherein the step (a) is carried out in water, and the step Z or (c) is carried out in water, an organic solvent or a mixture thereof.

[4] The process according to any one of claims 1 to 3, wherein the acidic condition in the step (a) is hydrochloric acid acidity.

[5] The production method according to any one of [1] to [4], wherein the high boiling point solvent is normaloctanol and Z or acetophenone.

[6] Dihydrochloride dihydrate of the compound represented by formula (5).